For the population science project, we assembled an interdisciplinary team, co-led by applied (epidemiologist) and basic (telomere biologist) scientists, to verify a novel tissue biomarker for prostate cancer prognosis that we discovered - telomere length variability in prostate cancer cells combined with short telomere length in cancer-associated stromal cells (telomere biomarker). In our prospective cohort study, men with this combination had 14-times the risk of prostate cancer death; men without this combination rarely died of their cancer over 15 years. Due to the fact that current prognostic factors inadequately distinguish between aggressive and nonaggressive disease, new prognostic biomarkers that inform beyond the currently used clinico-pathologic factors are needed to enhance treatment and surveillance decision-making. We will address this important unmet clinical need for improved risk stratification for prostate cancer patients. While our prior findings point to the clinical utility of the telomere biomarker, we have completed only the discovery phase. Here, we propose to; 1) Demonstrate the validity and reproducibility of an automated TELl-FISH method, our FISH-based telomere length measurement tool, using the same prospective cohort study in which we made our discovery. A valid and reproducible high-throughput method for measuring the biomarker is needed for the proposed epidemiologic study on prognosis, and in future epidemiologic studies on eariy detection and active surveillance. 2) Conduct a nested case-control study to verify the association between the telomere biomarker, assessed using automated TELl-FISH, and risk of lethal prostate cancer. 3) Determine optimal outpoints to refine the telomere biomarker for prognosis using both cohorts. 4) Evaluate whether prevalence of the refined telomere biomarker differs across age, race, and other patient characteristics. Differences in biomarker prevalence may inform the racial disparity in disease aggressiveness. We will extensively use the Pathology, Biostatistics, and Administrative Gores. We expect the telomere biomarker will be translated for clinical prognostic utility for prostate cancer in a trial in 5 years.